This is a Small Grant Program (R03) application for the lK08DKO2341-04 award entitled: "Biological role of hepatocyte growth factor-like protein (HGFL)." HGFL is a recently described serum glycoprotein with growth promoting and cytokine properties. Although in vitro studies have suggested that HGFL participates in the control of embryogenesis, fertility, inflammation, wound healing, hematopoiesis, and liver regeneration, the biological role for the protein remains largely unknown. To characterize the in vivo function of HGFL, the K08 award funded the use of gene-targeting techniques to successfully generate HGFL-deficient (HGFL -/-) mice. Data on genetic transmission, histological survey, and unchallenged growth have shown that HGFL -/- mice have normal embryogenesis, grow well into adulthood, and are fertile; organogenesis is intact, except for the development of cytoplasmic vacuolizations of hepatocytes in HGFL -/- livers. Activation of macrophages of HGFL -/- mice is delayed, but in the absence of HGFL other proteins appear to efficiently activate macrophages at later time points. Following acute mechanical and toxic challenges, the skin and gastrointestinal tract have unaltered healing despite the absence of HGFL. Therefore, our studies using HGFL -/- mice have demonstrated that HGFL is not essential for embryogenesis, fertility or healing following an acute injury. For the remainder of the K08 award, we plan to use these mice to directly test the additional proposed functions for the protein. Our hypotheses are: 1) HGFL induces tissue repair by inducing proliferation of epithelial cells, and 2) HGFL is an effector of the native immune response through the activation of macrophages. To address the first hypothesis, we will determine the regenerative response of the liver and gastrointestinal tract of HGFL -/- mice after partial hepatectomy and in models of acute and chronic inflammation. For the second hypothesis, we will subject HGFL -/- mice to bacterial challenges. Bacterial-host interactions will be determined by animal survival, ability of the host to suppress bacterial growth, and tissue inflammation following the infectious challenge. Our continued interaction with members of our K08 advisory committee and the additional support provided by this Small Grant Program will enhance our ability to carry out these experiments in the final phases of the K08 award and to make a transition to future independent studies which will define the biological role for HGFL in maintaining health and in the tissue-specific and systemic response to an injury.